Metabolic alkalosis may (1) occur as a primary disturbance (including those noted above); (2) arise as compensation of a primary respiratory acidosis (post hypercapnea); or (3) develop in the context of a mixed acid-base disturbance.

Clinical features

Primary metabolic alkalosis is "compensated " by hypercarbia, so that PCO2rises by 0.5-0.7 mm Hg for each 1 mM increase in plasma bicarbonate concentration. Thus, the expected (compensated) PCO2 is approximately equal to the sum of the plasma bicarbonate concentration plus 15.

As respiratory "compensation" corrects the alkalemia only in part, pulmonary underventilation together with low oxyhemoglobin dissociation (the Bohr effect) results in poor tissue oxygenation. In addition, metabolic alkalosis may also associated with ischemic cerebral or cardiac blood flow due to vasoconstriction; hypocalcemia due to avid binding of the divalent ion to albumin; and hypokalemia due to cellular shifts and urinary losses.

Key management points

Metabolic alkalosis can be categorized as "chloride responsive" or "chloride resistant." Patients with "chloride responsive" metabolic alkalosis may be acutely ill, and show signs of intravascular volume contraction. Laboratories will generally reveal a urine chloride concentration under 20 mM, and the patient will respond to an infusion of normal saline. Patients with "chloride resistant" metabolic alkalosis may appear chronically ill. Laboratories will generally reveal a urine chloride concentration above 20 mM, and the patient will not respond to an infusion of normal saline (or will improve only transiently).

2. Emergency Management

History

Elicit a history of vomiting, diarrhea (or other GI loss), polyuria, muscle weakness, GI and/or GU surgery and medications. In children, a prenatal history of polyhydramnios, recurring hospitalizations for dehydration, and early onset hypertension and/or growth retardation suggest a congenital renal tubular defect. Virilization suggests an endocrinopathy. In the adolescent, weight loss, muscle atrophy, bradycardia and hypothermia suggest an eating disorder. In adults, chronic use of diuretics, antacids and laxatives are common causes of metabolic alkalosis.

A blood gas, plasma chemistries and urine chloride measurement will aid in the diagnosis. Emergency management consists of providing adequate ventilation and the administration of intravenous saline to restore intravascular volume.

3. Diagnosis

Diagnostic criteria and tests

In addition to history (of excessive GI and/or urinary losses) and physical examination (especially changes in height, weight and vital signs), obtain a blood gas (including base excess), plasma chemistries and a measurement of urine chloride. The patient's underlying disease can often be categorized according to volume status, blood pressure, urine chloride concentration and response to chloride administration. Initial investigations should always include a measurement of all plasma electrolytes (sodium, potassium, chloride, phosphorus, Mg, calcium and uric acid), BUN and plasma creatinine, and plasma albumin. In select cases, initial investigations may also include measurement of plasma renin activity and aldosterone concentration.

Volume contracted/hypotensive/low urine chloride/chloride responsive

(Suspect based upon history and clinical examination): vomiting or other GI losses, villous adenoma, eating disorders, post-diuretic, cystic fibrosis.

Normal lab values

The expected respiratory "compensation" for primary metabolic alkalosis may be quantified using the following formulae:

PCO2 (mmHg) = plasma bicarbonate concentration (mM) +15

or

PCO2 (mmHg) = 40 + 0.7 (plasma bicarbonate concentration [mM]-24)

or

delta PaCO2 = 0.6 x delta standard base excess (SBE)

Establishing the diagnosis

Primary metabolic alkalosis is established by an interpretation of the blood gas, while the severity is determined by the pH and base excess (BE). If the history and physical examination alone are not diagnostic, then the differential diagnosis is unraveled according to the patient's intravascular volume status, blood pressure, urine chloride and response to the administration of chloride (as an example, by infusion of normal saline). Once the disorder is categorized according to the algorithm above, additional testing will confirm the diagnosis.

In volume-expanded patients with normal renal function and in whom saline administration is contraindicated, acetazolamide may be used to restore normal acid-base balance. In volume-expanded patients with poor renal function, hemodialysis using a high-chloride containing dialysate may improve the metabolic alkalosis.

5. Disease monitoring, follow-up and disposition

Expected response to treatment

Patients with chloride-responsive metabolic alkalosis should respond well to initial fluid therapy. However, the overall prognosis depends upon the underlying etiology. As an example, whereas patients with simple gastroenteritis may often be discharged from the emergency department with little or no follow-up, those will villous adenomas may require surgical resection of the lesion. The rare patient with chronic chloride-resistant metabolic alkalosis often requires highly specialized evaluation and more disease-specific management.

Incorrect diagnosis

The provisional diagnosis of acute, chloride-responsive metabolic alkalosis should always be re-considered whenever the patient does not improve (the plasma pH, bicarbonate, base excess and/or SID fails to normalize) with adequate administration of chloride. Chloride-resistance suggests inadequate replacement of ongoing and potentially chronic losses of chloride in the urine, skin or stool, and warrants further diagnostic testing.

5. Cushing's syndrome, CAH, or other adrenal disorder will require a thorough evaluation and treatment by an endocrinologist.

6. monogenetic forms of hypertension or other renal tubular disorders will require a thorough evaluation and treatment by a nephrologist.

Pathophysiology

While there are several equally correct ways of explaining metabolic alkalosis, perhaps the most straightforward and easily understood has been suggested by Peter Stewart, a Canadian physiologist. In the "Stewart" approach, metabolic alkalosis is due to an increase in the strong ion difference (SID) or to a decrease in total, non-volatile weak acids (such as albumin and phosphorus).

An increase in SID (approximately equal to the difference in plasma sodium and chloride) may be caused by the provision of excess cation (along with an anion that is metabolized by the liver, as in milk-alkali syndrome, and with the administration of sodium citrate, total parenteral nutrition, and blood products), the loss of chloride anions (vomiting, diuretics), or pure water desiccation. Plasma non-volatile weak acids may be depleted in nephrotic syndrome, liver failure and capillary leak syndrome.

Volume contraction stimulates the renin-angiotensin-aldosterone axis and potentially decreases the renal clearance of excess cations, further increasing the SID and worsening the metabolic alkalosis.

Epidemiology

Metabolic alkalosis is one of the most common electrolyte disturbances amongst hospitalized patients. Mortality rates of 45% have been reported in patients with an arterial blood pH of 7.55 and 80% when the pH was above 7.65.

(Congenital chloride diarrhea may sometimes be confused with Bartter's syndrome. The history of watery diarrhea and the finding of high stool chloride suggests the correct diagnosis and treatment [NaCl replacement].)

(These investigators followed patients with congenital chloride diarrhea and found a high incidence of chronic renal failure due to nephrocalcinosis. The investigators speculated that poor compliance with chloride supplementation contributed to chronic volume contraction and calcium precipitation.)

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